This application addresses an important area of interest to the National Institute on Drug Abuse (NIDA): The utilization of molecular targets for the treatment of drug addiction disorders. The specific aims of the proposal are: 1. To identify small molecule agonists of the Neurotensin 1 Receptor (NTR1) using a ?-arrestin high throughput, high content primary assay, and confirming hits using a variety of secondary assays. 2. To optimize two to three distinct lead compounds for NTR1 agonist activity via aim 1. This proposal will identify novel small molecule neurotensin receptor agonists that form the foundation for developing drugs to treat and prevent methamphetamine abuse. It addresses an immediate goal of the National Institute on Drug Abuse that new approaches are needed for treating methamphetamine addiction (NIDA Research Report Series, 2006). We propose to identify novel small molecule neurotensin receptor agonists by high content screening of large libraries of compounds using a primary assay that is cell based and exploit the ability of an arrestin-green fluorescent protein reporter to directly recognize the activated state of the NTR1. Lead optimized NTR1 agonists from within this discovery program will be applicable for translational studies aimed towards the development of novel medical therapies to treat amphetamine abuse. PUBLIC HEALTH RELEVANCE: Drug addiction is a major social and economic problem for the US. It is now believed that drug abuse is best classified as a disorder of the brain, and as such should be amenable to medical therapy. Amphetamine derivatives like methamphetamine are widely abused drugs and recent evidence indicates that amphetamine use can be suppressed by peptide agonists that activate neurotensin receptors. The goal of this proposal is to identify small molecule neurotensin receptor agonists. These compounds will be used as tool compounds to study the pathways involved in drug seeking behaviors and may provide the basis to develop novel drug therapies to treat amphetamine abuse.